Serotonin, a neurotransmitter with mixed and complex pharmacological characteristics, was first discovered in 1948 and subsequently has been the subject of substantial research. Serotonin, also referred to as 5-hydroxytryptamine (5-HT), acts both centrally and peripherally on discrete 5-HT receptors. 5-HT Receptors are presently delineated into three major subclassifications - 5-HT.sub.1, 5-HT.sub.2 and 5-HT.sub.3 - each of which may also be heterogeneous. Receptors of the 5-HT.sub.3 subclass pervade autonomic neurons and appear to regulate the release of a variety of neurotransmitters in the gastrointestinal, cardiovascular and central nervous systems.
5-HT.sub.3 receptors are located in high densities on neurons associated with the emetic reflex and drugs which block the interactions of serotonin at the 5-HT.sub.3 receptor level, i.e., 5-HT.sub.3 receptor antagonists, possess potent antiemetic properties. Such antagonists demonstrate utility for counteracting the emetic effects of cancer chemotherapy and radiotherapy (see Drugs Acting on 5-Hydroxytryptamine Receptors: The Lancet Sep. 23, 1989 and refs. cited therein.).
Functional bowel disorders are prevalent in much of the industrialized world. Chronic gastroesophageal reflux disease alone may be present in as much as 15% of the population. Use of prokinetic agents is one of the most effective methods known for treating such disorders. Because many 5-HT.sub.3 antagonists possess prokinetic properties and are relatively free from side effects they are particularly useful in the treatment of gastrointestinal diseases (see Reynolds R. C. Prokinetic Agents: A Key in the Future of Gastroenterology. Gastroenterology Clinics of North America 1989; 18: 437-457).
5-HT.sub.3 receptors are present in those areas of the brain which control mood, emotion, reward and memory. 5-HT.sub.3 receptor antagonists reduce mesolimbic dopamine levels, a necessary property for antipsychotic activity. Such antagonists also increase cholinergic tone in the limbic-cortical region, which may explain their cognitive enhancing effects. In addition, 5-HT.sub.3 antagonists possess anxiolytic properties, demonstrate potential for use in the treatment of dependency disorders and are under investigation in patients with schizophrenia (see article from The Lancet previously cited).
There is evidence that 5-HT.sub.3 receptors mediate nociceptive input to afferent neurons (see Glaum, S., Proudfit, H. K., and Anderson, E. G. 1988; Neurosci, Lett, 95, 313). 5-HT.sub.3 antagonists may therefore be of value in the control of pain, particularly migraine (see Peatfield R. 1988; Drugs and the Treatment of Migraine. Trends. Pharmacol. Sci. 9: 141).
The 5-HT.sub.3 receptor antagonist ICS 205-930 inhibits arrhythmias in a variety of animal models and exerts mixed class III and class I antiarrhythmic properties in ventricular myocytes (see Scholtysik, G., Imoto, Y., Yatani, A. and Brown, A. M. 1988; J. Pharmacol. Exp. Ther. 245, 773 and references therein). 5-HT.sub.3 antagonists may therefore be of use in treating or preventing arrhythmias.
European Patent Application No. 83301158.8, published Nov. 9, 1983 as No. 0 093 488, discloses phthalimidine and dihydroisoquinolinone dopamine receptor antagonists of the formula: ##STR3## in which, inter alia, R.sup.2 and R.sup.3 can each be hydrogen, halogen, hydroxy, alkoxy, C.sub.1-6 alkyl, nitro or amino or aminocarbonyl (which can be substituted by one or two C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl or C.sub.3-8 cycloalkyl(C.sub.1-4)alkyl) or C.sub.1-7 acylamino;
r is 1 or 2;
p and q are 0, 1 or 2;
R.sup.4 is C.sub.1-7 alkyl or (CH.sub.2).sub.s -R.sup.6 where s can be 0 and R.sup.6 is C.sub.1-6 cycloalkyl or (CH.sub.2).sub.t R.sup.7 where t is 1 or 2, and R.sup.7 is phenyl optionally substituted by one or two substituents selected from C.sub.1-4 alkoxy, trifluoromethyl, halogen, carboxy, esterified carboxy, and C.sub.1-4 alkyl optionally substituted by hydroxy, C.sub.1-4 alkoxy, carboxy, esterified carboxy or in vivo hydrolyzable acyloxy or is thienyl; their pharmaceutically acceptable salts, solyates, N-oxides, and their use in treating emesis, impaired gastro-intestinal motility (including ulcers) and CNS disorders (e.g., psychosis) and as analgesics in the treatment of migraine. It further discloses a process for preparing N-substituted dihydroisoquinolinones which involves reacting an azabicycloamine nucleophile (e.g., endo-amino-9-methyl-9-azabicyclo[3.3.1]nonane) with an appropriate homophthalic anhydride, homophthalic acid derivative, or 2-(2-substituted ethyl)benzoic acid derivative (e.g., ethyl 2-(2-bromoethyl)benzoate).
U.S. Pat. No. 4,959,367, issued Sep. 25, 1990, discloses 4-oxobenzotriazine and 4-oxoquinazoline 5-HT.sub.3 receptor antagonists of the formula: ##STR4## in which
X is N or CH;
R.sup.1 and R.sup.2 can be, inter alia, hydrogen, halogen, hydroxy, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro or amino or aminocarbonyl (which can be substituted by one or two C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl or C.sub.3-8 cycloalkyl(C.sub.1-4)alkyl) or C.sub.1-7 acylamino; and Z is a group selected from formula (a), (b) and (c): ##STR5## in which
n is 2 to 3;
p is 1 to 2;
q is 1 to 3;
r is 1 to 3;
and R.sup.3 and R.sup.4 is C.sub.1-4 alkyl;
their pharmaceutically acceptable salts and their use in treating emesis (especially emesis caused by cytotoxic agents or radiation induced nausea and vomiting), migraine, cluster headaches, trigeminal neuralgia, visceral pain, arrhythmias, CNS disorders (e.g., anxiety, psychosis, drug withdrawal syndrome, obesity) and gasro-intestinal disorders such as irritable bowel syndrom, retarded gastric emptying, dyspepsia, flatulence, oesophageal reflux and peptic ulcer. It further discloses a process for preparing N-substituted 4-oxoquinazolines which involves reacting an appropriate N-substituted 2-aminobenzamide (e.g., (endo)-N-(8-methyl-8-azabicyclo[3.3.1]oct-3-yl)-2-amino-1-benzamide) with formic acid or triethyl orthoformate.
King, K. D.; Dabbs, S.; Bermudez, J.; Sanger, G. J. J. Med. Chem. 1990, 33, 2942-2944 discloses 5-HT.sub.3 receptor antagonists of the formula: ##STR6## in which
X is N or CH;
R.sup.1 is 1-azabicyclo[2.2.2]oct-3-yl or (endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl);
R.sup.2 is hydrogen, nitro or amino; and
R.sup.3 is hydrogen or chlorine. The document further discloses that when X is CH, 5-HT.sub.3 receptor potency is substantially reduced.
The disclosures of these and other documents referred to throughout this application, e.g., in the Pharmacology section of the Detailed Description of the Invention, are incorporated herein by reference.